The Benefits and Risks of Statin Therapy in Ischemic Stroke: A Review of the Literature
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266274
Source of Support: None, Conflict of Interest: None
Keywords: Benefits, cardiovascular diseases, intracranial hemorrhage, ischemic stroke, risks, statin
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) which catalyzes the rate-limiting step in cholesterol synthesis, and are thus effective in the treatment of dyslipidemia. Several large, double-blind randomized clinical trials have demonstrated that statins can reduce the risk of cardiovascular events such as heart attack., Statins have been used as first-line drugs for reducing the risks of mortality and morbidity of cardiovascular diseases. In addition, statins have been reported to produce neuroprotective effects in many neurovascular diseases such as stroke, and neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and multiple sclerosis. However, there are concerns regarding the adverse effects of statin therapy, such as rhabdomyolysis, intracerebral hemorrhage (ICH), liver toxicity, and new-onset diabetes.,, Therefore, it is important to evaluate the benefits and risks of statin therapy for patients with cardiovascular and cerebrovascular diseases.
Stroke is a leading cause of mortality and morbidity worldwide, and represents a major public health problem. Lipid abnormalities are commonly associated with stroke patients. Statins are effective for primary and secondary stroke prevention,, and the benefits of statins have been found to be associated with the lipid-lowering effect., In addition, statins have pleiotropic effects that potentially benefit patients who have in ischemic stroke, including an anti-oxidative effect, an anti-inflammatory effect, the promotion of endothelial NO production, inhibition of platelet aggregation, of oxidized LDL-C, and an enhancement of angiogenesis.,,,, However, statin use may be associated with an increased risk of ICH, which reduces the beneficial effect of statins in stroke patients. Other studies have reported that statin use is associated with a significant reduction in all stroke and all-cause mortality; however, it is not significantly associated with ICH., Therefore, controversies remain concerning the safety of statin therapy in stroke patients. In this review, we summarize the beneficial effects of statin therapy in patients with ischemic stroke and discuss the potential risks of ICH associated with statin therapy.
Statin therapy is associated with a significant beneficial effect in ischemic stroke., Several studies have demonstrated the beneficial effects of pre-stroke and post-stroke statin use in ischemic stroke.,,, Good statin adherence is associated with a better clinical outcome, and statin withdrawal is associated with worse functional outcomes in patients with ischemic stroke., Therefore, statin use is generally believed to be beneficial in ischemic stroke.
Several studies have shown that statin use is not associated with significant improvement of functional outcome in patients with ischemic stroke.,, Small sample sizes in these studies may contribute toward the unfavorable results of statin use in ischemic stroke. In this article, we searched PubMed for studies with a relatively large sample size of statin use in ischemic stroke, which were published in English within the past 10 years (2006–2016). The following key words were used “ischemic stroke” and “statin,” or “hydroxymethylglutaryl-CoA reductase inhibitors.” We selected clinical studies with a large sample size (≥1000) by reviewing the articles and their references. Most studies support the beneficial effect of statin use in ischemic stroke [Table 1].
Several experimental studies have shown that statin pretreatment increases cerebral blood flow and reduces cerebral infarction size during cerebral ischemia., Consistent with these animal studies, several clinical studies have reported that pre-stroke statin use is associated with more collaterals or a smaller infarction size in patients with acute cerebral ischemia., Increasing evidence has shown that pre-stroke statin use reduces the risk of initial and recurrent stroke and produces beneficial effects on the severity, functional outcome, and short- and long-term mortality in patients with ischemic stroke.,,, Ford et al. reported that pre-stroke statin use was associated with greater early reperfusion in 31 patients with ischemic stroke, who underwent reperfusion magnetic resonance imaging scans within 4.5 and 6 hours after stroke onset. Therefore, the beneficial effects of statin therapy may be due to the reduction of cerebral infarction by enhancing early reperfusion.
In the medical group of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, the absence of statin use at the enrollment was found to be independently associated with an increased risk for recurrent ischemic stroke, suggesting that statin use may reduce the risk of stroke. Consistent with this idea, several clinical trials have shown that pre-stroke statin use reduces the risks for an initial or recurrent stroke.,, A prospective, randomized trial performed by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators found that statin use resulted in a 16% reduction of nonfatal or fatal stroke in patients who had recent stroke or transient ischemic attack. The cholesterol-lowering effect may attribute to its beneficial effect of statin in stroke risk reduction. Because several epidemiological studies have shown that there is no significant association between the incidence of stroke and plasma total cholesterol levels,, the pleotropic effects of statins, such as anti-oxidative, anti-inflammatory, anti-thrombotic, and angiogenetic effects, may contribute to reduce stroke risk by statins.
The beneficial effect of pre-stroke statin use is further demonstrated by several studies which have shown that pre-stroke statin use is associated with a mild stroke severity., However, several studies failed to detect the beneficial effect of pre-stroke statin use on stroke severity.,,,, However, a relatively small sample sizes of these studies may account for the negative results of pre-stroke statin use in stroke severity. In a meta-analysis from data including a large sample size of 6806 patients with ischemic stroke, pre-stroke statin use was found to be associated with milder initial stroke severity compared with non-statin use. Furthermore, in a recent retrospective study including 8340 patients with acute ischemic stroke, pre-stroke statin use was independently associated with lesser stroke severity at presentation.
Most studies have investigated the effect of pre-stroke statin use on short-term functional outcome at discharge, 7 days, or 90 days after stroke using the modified Rankin scale.,,,,,,,,, Although most of these studies found that pre-stroke statin use was associated with favorable functional outcome in ischemic stroke patients,,,,,,,,, some studies also reported that pre-stroke statin use resulted in no significant improvement of functional outcome.,, In randomized SPARCL trial, recurrent stroke patients with pre-stroke statin use (n = 197) exhibited a tendency toward a good functional outcome compared with the placebo control (n = 257). However, no significant difference was found (P = 0.0647). Some analyses may be not sufficiently powered to detect the favorable outcome of stations due to small sample sizes. Most studies with a large sample size support the beneficial effect of pre-stroke statin use in ischemic stroke [Table 1]. For example, in a meta-analysis including 10172 patients with acute ischemic stroke, pre-stroke statin use is associated with improved functional outcome. A recent systemic review including more patients with acute ischemic stroke (n = 30942) supported the conclusion that pre-stroke statin use is associated with favorable function outcome in acute ischemic stroke. Furthermore, a recent large retrospective cohort study (n = 8340) reported that pre-stroke statin use was independently associated with a better early function recovery at discharge in patients with acute ischemic stroke.
In addition to a better functional outcome, pre-stroke statin use is associated with decreased short-term mortality at discharge or within 90 days after stroke in patients with ischemic stroke.,,, Three meta-analysis studies have confirmed the beneficial effect of pre-stroke statin use on the survival of patients with ischemic stroke.,, Furthermore, Ni Chroinin et al. reported that pre-stroke statin use was associated with good functional outcome and improved 1-year survival in patients with ischemic stroke.
Several studies have demonstrated that hypercholesterolemia is an independent risk factor for ischemic stroke due to atherosclerosis, for which LDL-C is important in the development.,, The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guideline recognizes that lower LDL-C levels are associated with a reduced risk for atherosclerotic cardiovascular diseases (ASCVD), and recommends the use of statins to reduce ASCVD risk. Because embolic stroke is less associated with cholesterol levels, statin therapy is less effective in patients with embolic stroke. Although several studies did not specifically indicate the type of ischemic stroke,,,, many clinical studies reported the beneficial effect of statin therapy in patients with ischemic stroke including thrombotic stroke, but not embolic stroke.,,,, However, it has been reported that treatment with rosuvastatin (5 mg for 6 months) stabilized atherosclerotic aortic plaque with marked LDL-C reduction in acute ischemic stroke patients with dyslipidemia and large atheromatous aortic plaques, suggesting that statins may be used for the prevention and treatment of aortogenic brain embolism.,
The beneficial effects of statin therapy initiated after stroke during hospitalization have been reported in patients with ischemic stroke. Most studies examined the effect of post-stroke statin use on functional outcome at discharge or at 90 days post-stroke stroke., Post-stroke statin use has been found to be associated with good functional outcome (mRS, 0–2) in patients with ischemic stroke.,,,,,,,, In addition, two meta-analyses have shown that post-stroke statin use is associated with good functional outcome in patients with ischemic stroke., However, in a prospective cohort study, Yeh et al. reported that there was no significant association between post-stroke statin use during hospitalization and functional outcome in patients with stroke-associated infection. However, the different disease severity included in the study by Yeh et al. may limit the identification of the positive association between post-stroke statin use and a favorable functional outcome in patients with ischemic stroke. Although most studies with a large sample size support the beneficial effect of post-stroke statin use in ischemic stroke [Table 1], a prospective, randomized, controlled trial is required to determine the definite role of post-stroke statin use on the functional outcome of in ischemic stroke patients.
Several observational studies reported that post-stroke statin therapy during hospitalization is associated with improved survival at discharge or at 90 days after stroke.,,,,, The beneficial effect of post-statin use on the survival of ischemic stroke patients has been further confirmed by meta-analysis studies., In addition, post-stroke statin use has been reported to be associated with a long good functional outcome and improved survival at 1 year in patients with ischemic stroke., In a large observation study (n = 12689), statin use during stroke was associated with an 1-year survival in patients with acute ischemic stroke. Recent results from the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study showed that statin therapy after ischemic stroke was associated with a reduced risk of major adverse cardiac events and lower risk of all-cause mortality during the 2-year period after hospitalization in patients with ischemic stroke. In a retrospective observational study including 794 first-ever acute ischemic stroke patients, statin use after hospital discharge was associated with an improved 10-year survival. The beneficial effect of post-stroke statin therapy is further supported by a randomized controlled study showing that statin withdrawal is associated with an increased risk of deaths and worse functional outcomes in patients with ischemic stroke. A large observational study has reported that patients who underwent statin withdrawal after ischemic stroke were associated with a poor functional outcome at discharge. A meta-analysis further confirmed that statin withdrawal is associated with a poor functional outcome in patients with ischemic stroke. Moreover, good statin adherence has been found to be associated with a better clinical outcome in patients with acute ischemic stroke.
In a SPARCL trial, compared with placebo controls, the high-intensity statin (atorvastatin 80 mg) initiated after a stroke or transient ischemic attack (TIA) resulted in a 16% reduction of nonfatal and fatal stroke and a 20% reduction of major cardiovascular events after 5-year follow-up. This suggesting that high-intensity statin therapy is beneficial in reducing the risk for stroke. High-intensity statin therapy is defined by a reduction of LDL-C of more than 50% of the baseline values after treatment with atorvastatin at the dose of 40–80 mg or rosuvastatin at the dose of 20–40 mg. The 2013 ACC/AHA cholesterol guideline recommends the use of moderate- or high-intensity statin therapy in 4 groups of individuals: (1) those with clinical ASCVD including stroke, (2) those with primary elevation of LDL-C >190 mg/dl, (3) diabetic patients aged 40–75 years with LDL-C between 70 and 189 mg/dl, or (4) those aged 40–75 years with 10-year ASCVD risk of >7.5%. In addition, high intensity-statin therapy reduces all-cause mortality in patients with recent acute coronary syndromes when compared with moderate-intensity statin therapy. In a large observational study (n = 12689), high dose statin (>60 mg/day) during hospitalization improved 1-year survival in patients with acute ischemic stroke compared with low dose statin (<60 mg/day). However, results from the PROSPER study reported that, after adjustment for confounding and potential bias in the patient population, high-intensity statin therapy did not reduce major adverse cardiac events and mortality during the 2-year period after hospitalization in patients with ischemic stroke compared with low/moderate statin therapy. In the study by O'Brien et al., patients in the statin treatment group were determined based on the basis of statin prescription at discharge. Their adherence to medication after hospital discharge was not followed up. Therefore, no beneficial effect of high-intensity statin therapy in the study by O'Brien et al. may be associated with statin withdrawal because it has been found that statin withdrawal even for a short period of 3 days results in worse functional outcome in patients with ischemic stroke. Furthermore, in a meta-analysis study including 170,000 participants in 26 randomized trials, more aggressive statin treatment versus less aggressive treatment reduced cardiovascular events in patients with a history of ischemic stroke, including coronary death or nonfatal myocardial infarction, coronary revascularization, and ischemic stroke. In a prospective study of 436 patients who were discharged after acute ischemic stroke, aggressive statin treatment improved the long-term functional outcome at 1 year after stroke more than less aggressive statin treatment. Therefore, aggressive treatment with high-dose statin is likely associated with a favorable functional outcome and improved survival in patients with ischemic stroke.
The 2013 ACC/AHA cholesterol guideline recommends that high-intensity statin should be initiated for the primary and secondary prevention of ASCVD in patients with high risk of cardiovascular risks, especially those who can tolerate high-intensity statins without statin-associated adverse reactions. In a recent study including patients with high cardiovascular risk (n = 541,221), approximately 15% of the patient population initiated the therapy with high-intensity statins, and the mean duration of treatment was 21 months. For patients with ischemic stroke, a long-term treatment with high-intensity statins is recommended. However, there is no consensus regarding the treatment duration of high-intensity statins in patients with ischemic stroke to date. Most studies examined the beneficial effect of statin therapy for a relative short period of time (during hospital or 90 days) [Table 1]. It is known that statin discontinuation is associated with worse clinical outcomes in patients with ischemic stroke.,, However, it has been reported that the rate of medication adherence is low, especially in patients with high cardiovascular risks., Adverse reactions and loss of therapeutic benefits may underlie the reasons for nonadherence to statin therapy., Future studies should be performed to determine the optimal duration of high-intensity statin therapy to prevent adverse cardiovascular events in patients with ischemic stroke.
Different statins exhibit differences in terms of pharmacokinetics, pharmacodynamics, clinical efficacy, and side effects. Atorvastatin is one of the most commonly used statins, but rosuvastatin has achieved greater reduction of LDL-C and a better clinical outcomes than other statins. Atorvastatin and rosuvastatin are common statins used to investigate the efficacy of statin therapy, especially high-intensity statin therapy in patients with ischemic stroke. However, most studies include atorvastatin and/or rosuvastatin, and few studies have compared the efficacy both in patients with ischemic stroke. Recently, Arshad et al. reported that compared with atorvastatin (10 mg), rosuvastatin (5 mg) produced a greater reduction of serum LDL-C in patients with type 2 diabetes, hypertension, myocardial infarction, or stroke. Switching from rosuvastatin to atorvastatin led to fewer patients achieving LDL-C goal and a greater risk for MACE. Furthermore, Schuetz et al. reported that rosuvastatin was superior to atorvastatin in preventing cardiovascular events. These findings suggest that rosuvastatin may be a better than atorvastatin in patients with high cardiovascular risk. However, no clinical studies have been performed to investigate the difference in the efficacy between atorvastatin and rosuvastatin in patients with ischemic stroke to date.
Several studies have shown that low serum levels of total cholesterol are associated with a high risk for ICH.,, The cholesterol-lowering effect of statin may be responsible for the high risk of ICH associated with statin therapy. However, it has been reported that neither the LDL cholesterol level or statin use are not associated with the risk of ICH. The occurrence of ICH is not found to be associated with LDL cholesterol levels at the baseline or during statin treatment. Other pleiotropic effects of statins have been proposed to contribute to the hemorrhagic risk. Statins can have antithrombotic activity by inhibiting platelet aggregation, and thus result in reduced thrombosis and hemorrhage., In addition, statin may cause arterial muscles necrosis and microaneurysmal formation, thus leading to hemorrhage.,
In the SPARKL trial, statin therapy was found to be associated with an increased risk for ICH. Hemorrhagic stroke was more frequently found in patients treated with atorvastatin, especially in those with a hemorrhagic stroke as an entry event, in men, and in elderly patients. A recent meta-analysis of randomized controlled trials have found that high-dose statin therapy is associated with a high risk of ICH in patients with cardiovascular diseases. Furthermore, there is concern on increased risk of ICH with statin use in ischemic patients treated with thrombolysis. Meier et al. found that prior statin use is associated with a high incidence of ICH in patients with ischemic stroke who received intra-arterial thrombolysis. High dose of statin use is associated with a high incidence of symptomatic ICH in patents with ischemic stroke after intravenous thrombolysis. Furthermore, in a systemic review pre-stroke statin use is found to be associated with an increased risk for ICH in patients with acute ischemic stroke, despite favorable functional outcome. For patients with ICH, statin use might be associated with an increased risk of recurrent hemorrhage. It has been reported that statin use is associated with an increased ICH volume in patients with spontaneous brain hemorrhage. In patients with ICH, statin use is independently associated with microbleeds, especially the corticosubcortical microbleeds.
However, the association of statin use with the risk of ICH is not supported by many studies. In a large retrospective cohort study including 17872 patients with acute ischemic stroke, statin use is was not associated with an increased risk of ICH. Several meta-analyses have found that statin therapy was not associated the risk for developing ICH.,, In a recent cohort study including more than 1 million participants without a previous history of stroke, statin use was not associated with the risk of ICH. These findings suggest that statins can be safely used in patients with ischemic patients without an increased risk for ICH. In addition, several studies have demonstrated no significant association between statin use and ICH in patients with acute ischemic stroke who underwent thrombolysis treatment.,, However, because the findings were largely obtained from observational studies, well-designed large randomized control trials are required to confirm the association of statin use with ICH in patients with acute ischemic stroke.
Although the concern regarding the association of statin use with the risk of ICH remains, in a recent meta-analysis of 1652 ICH patients exposed to statins and 5309 ICH patients without statin use, prior statin use was not associated with an increase in the short-term mortality, a unfavorable functional outcome, or post-ICH hematoma volume at admission. Growing evidence has shown that statin use before ICH, at the onset of ICH or after ICH, is associated with favorable outcome of ICH patients. For examples, several studies have demonstrated that prior use of statins is associated with good functional outcomes during hospitalization, and at 1 month, 3 months, and 6 months  after ICH, although this favorable outcome was not identified in some small clinical studies., The favorable outcome of prior statin use in ICH patients was further confirmed by a meta-analysis showing that prior statin use was associated with good outcome and reduced mortality after ICH. In a retrospective analysis of 190 ICH patients exposed to statin and 236 statin-free ICH patients, statin use at the onset of ICH or during the acute hospitalization (within 72 h after ICH) is associated with reduced mortality and disability in-hospital and at 12 months after ICH. Furthermore, in a meta-analysis of 3455 ICH patients exposed to statin and 11821 ICH patients not exposed to satin, continuing statin use after ICH onset is associated with an improved outcome in ICH patients.
In support of the idea that statin use is associated with good outcome after ICH, several studies have reported that statin discontinuation is associated with a poor outcome and survival after ICH., In a retrospective cohort study of 3481 patients with ICH, Flint et al. reported that statin use during hospitalization was associated with improved outcomes after ICH, and the cessation of statin use was associated with worsened outcomes after ICH. Other studies confirmed that discontinuation of statin use may be associated with a poor outcome after ICH.,,
Even though statins are considered to be safe drugs, statin therapy is associated with some side effects such as hepatotoxicity, myopathy, rhabdomyolysis, and new onset diabetes (NOD). Because elevations in hepatic transaminase levels occurred in <1.5% of the patients with high-intensity statin therapy over 5 years, routine monitoring hepatic transaminase levels does not detect or prevent serious liver injury. Routine monitoring hepatic function. Thus, has been considerably decreased in the clinic. It is recommended that statins, if indicated, should not be avoided in patients with preexisting liver dysfunctions such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, compensated cirrhosis, and compensated chronic liver disease. Muscle-associated symptoms, such as myopathy and rhabdomyolysis, occurred in at least 5% of the patients treated with statins in the clinic., In one prospective randomized trial of 420 statin-free people, the incidence of muscle pain was 9.4% for individuals with high-intensity of atorvastatin (80 mg/day) for 6 months, compared to 4.6% for those with placebo. However, it is reported that a majority (92%) of patients with muscle complaints during statin therapy can still continue statin treatment, and only 0.5% of patients who complained of muscle problems had to discontinue statin therapy. However, if rhabdomyolysis occurs, statin therapy must be stopped. In addition, several studies have reported that statin use was not associated with more hepatic or muscular adverse events in patients with acute ischemic stroke compared to statin nonusers. Therefore, the hepatic and muscular adverse effects are not major concerns of statin therapy in patients with ischemic stroke.
However, meta-analyses have shown that statin therapy is associated with a 9% increase in the risk for NOD, and high-intensity statin therapy is associated with additional 12% increase in NOD. Because diabetes is known to increase the risk of cardiovascular disease, caution should be taken when high-intensity statins are used in patients with ischemic stroke. Four risk factors for NOD have been identified in the TNT (Treating to New Targets) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) trials as follows: fast blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, hypertension, and obesity (body mass index >30 kg/m 2). It has been reported that high-dose atorvastatin (80 mg) is not associated with an increased risk of NOD in patients with 0–1 of the 4 risk factors compared with moderate-dose statin therapy. However, high-dose atorvastatin increased NOD by 24% in patients with 2–4 of these risk factors. Despite an increased risk of NOD, high-dose atorvastatin reduced major cardiovascular events in patients with high risk for NOD. Similarly, the JUPITER (Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study reported that rosuvastatin (20 mg) was associated with an increased risk of NOD in patients with risk factors for diabetes compared with placebo, and the benefits of rosuvastatin exceeded the risks of NOD.
The benefits of statin therapy have been established for patients with ischemic stroke [Table 1]. Moderate- or high-intensity statin therapy is recommended for use in 4 groups of patients according to the 2013 ACC/AHA cholesterol guideline. For patients with ischemic stroke, growing evidence supports the use of high-intensity statin therapy because high-intensity statin therapy is found to be associated with favorable outcomes.,, However, although an increasing numbers of studies have shown that there are no significant associations between statin use and an increased risk for ICH, and that statin use is associated with favorable outcome in patients with ischemic stroke,,, there are still concerns of ICH associated with statin therapy.,, Statin use appears to be associated with an increased risk for ICH in patients with previous history of ICH and in particular cerebral amyloid angiopathy., Precaution should be taken while initiating statin therapy in patients with high ICH risk, who are not exposed to statins. For patients who are on statin use during ICH onset, continuing statin use is recommended, and statin cessation may be considered after continuing use of 6–12 months. For patients with high risk factors for NOD, no changes in statin therapy is recommended to current clinical practice in patients at a risk for diabetes because of the benefits of statin therapy in cardiovascular event reduction.
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